Mechanical stress (e.g., exercise) triggers an increase in prostaglandins (PCs) in skeletal muscle and bone through activation of the enzyme cyclooxygenase (COX). There is strong evidence from studies of animals that this increase in PGs is essential for bone formation. When COX activity is inhibited by non-steroidal anti- inflammatory drugs (NSAIDs), such as ibuprofen (IBUP), the bone formation response is almost completely abrogated. Acetaminophen (ACET) is an analgesic that has traditionally been thought to have only weak, if any, inhibitory effects on COX activity. However, emerging evidence suggests that ACET may, indeed, inhibit COX activity in some tissues. If this occurs in muscle and bone, it is possible that mechanical signaling in these tissues would be impaired by ACET use. The only study to address this found that both IBUP and ACET blunted the increases in PGs in response to a single bout of resistance exercise in human skeletal muscle, and this was accompanied by a blunted increase in fractional muscle protein synthesis. It is not known whether the observed effects of ACET and IBUP to attenuate muscle PG production and protein synthesis in response to a single bout of exercise persist with repeated bouts of exercise (i.e., exercise training), or whether ACET and IBUP act through similar mechanisms. It is also unknown whether ACET impairs the osteogenic responses to mechanical loading. Thus, the primary aims of the proposed studies are to determine the effects of ACET on the musculoskeletal adaptations to exercise training and to evaluate potential mechanisms by which ACET influence muscle metabolism; an IBUP arm will be included to gain insight into whether ACET and IBUP act through similar mechanisms. Men (n=31), aged 60+ yr, will undergo 4 mo of supervised, progressive exercise training that will include high-intensity weight lifting and weight- bearing exercises to stimulate muscle hypertrophy and bone formation. Participants will be randomized to ACET (1000 mg/d; n=12), IBUP (400 mg/d; n=7), or PLAC (n=12). It is hypothesized that exercise-induced increases in fat-free mass and bone formation markers will be attenuated by the use of ACET compared with PLAC. We further hypothesize that expression of critical components of the AKT/mTOR signaling pathway (e.g. mTOR, GSK-3) will respond discordantly to exercise + PLAC when compared with exercise + ACET or + IBUP. The AKT/mTOR pathway is an important regulator of skeletal muscle protein synthesis and degradation and responds to exercise stimuli and COX-inhibition. The importance of this study centers on the widespread use of analgesics among the elderly, a population at increased risk for sarcopenia, osteoporosis, and physical impairment. Although high-intensity exercise has the potential to improve muscle mass, strength, physical function, and bone mineral density in the elderly, it is possible that the use of ACET mitigates these musculoskeletal adaptations by interfering with mechanical signal transduction. [unreadable] [unreadable] [unreadable]